We have defined a new approach to the use of monoclonal antibodies for diagnosis and therapy of tumor in lymph nodes: delivery to the nodes via lymphatic vessels after subcutaneous injection. To establish a firm pharmacokinetic basis for this approach, we first studied antibodies to normal cell types in the mouse lymph node. In vitro binding characteristics were combined with in vivo pharmacological parameters to develop a quantitative understanding of the delivery process using the SAAM computer modeling system. Armed with that background information, we then demonstrated and analyzed specific uptake in lymph node metastases of a guinea pig tumor. The approach was extended to include endoscopic techniques for reaching lymph node groups not accessible by subcutaneous injection. Imaging studies were followed up with attempts at therapy. For diagnosis of early metastatic tumor in the nodes, the lymphatic route can provide higher sensitivity, lower background, lower systemic toxicity, and faster localization than the intravenous route. It will also minimize the problem of cross-reactivity with antigen present on normal tissues. This technique has been applied to detection of lymph node metastases in clinical stage II malignant melanoma and cutaneous T-cell lymphoma (CTCL) (with very good results) . Similar protocols have been approved for breast carcinoma, small cell lung carcinoma, and non-small cell lung carcinoma. Our studies of CTCL produced the most efficient antigen-specific imaging yet achieved in humans by any technique. The longer term aim is to understand the pharmacology of monoclonal antibodies and other ligands in order to develop criteria for rational molecular design of biological antitumor agents. This work on "immunolymphoscintigraphy" has been followed up clinically by others, who recently published encouraging results on diagnosis of axillary metastases of breast cancer.